NeuroSearch reports the conclusions from the Multiple Ascending Dose study (MAD). The study was a randomised, placebo-controlled, double-blind study to evaluate the safety, tolerability and pharmacokinetics relating to multiple ascending doses of Huntexil® in 36 healthy male and female subjects. Considering the benign safety and tolerability seen with Huntexil® in large Huntington’s disease studies with 45 mg twice daily, the MAD study was aimed at exploring the tolerability of even higher doses before embarking on the planned Phase III study.
In addition, the aim of the MAD study was to further evaluate the effect of Huntexil® on the QT interval using enhanced ECG monitoring to obtain valuable information for the thorough QTc study, in which the investigation of a supratherapeutic dose is required per guidelines.
The study has completed its active phase, and a dose of 90 mg twice daily is concluded to be the maximum tolerated dose. It was planned also to investigate a dose of 112.5 mg twice daily, but due to tolerability issues observed at 90 mg twice daily, the study was stopped at this dose.
The study showed that ascending doses of Huntexil® resulted in increasing numbers of incidences as well as increasing severity and duration of previously seen adverse events, such as nausea, headache, dizziness and vomiting. In addition, psychiatric signs and symptoms were reported at the dose of 90 mg twice daily. Further, Huntexil® caused a dose-dependent QT prolongation that, in the healthy subjects, reached a level of clinical concern for both the 67.5 and the 90 mg twice daily groups compared to placebo. The 45 mg twice daily dose was well tolerated, even though QT prolongation at this dose level was higher than seen in previous large clinical studies.
The planned Phase III programme for Huntexil®, including the PrimeHD study, will be adjusted to reflect the new information, although the final conclusions have yet to be made in this regard.
Based on the findings on the QT interval, NeuroSearch will with immediate action implement appropriate additional safety measures in the ongoing clinical programmes, including Open-HART (the US) and Compassionate Use (Europe), where a dose of 45 mg twice daily is administered.
Karin Garre, Executive Vice President & Chief Development Officer,
telephone: +45 2068 6888